Valentino, Leonard A.

Background and Purpose: Bolus infusion (BI) of recombinant FVIIa (rFVIIa) is effective for the treatment of bleeding and surgical prophylaxis in congenital hemophilia A or B patients with FVIII or IX inhibitors. In principle, continuous infusion (CI) of rFVIIa could maintain the hemostatic effect at a steady state while avoiding the peaks and troughs of repetitive BI. The purpose of this study was to compare the efficacy and safety of rFVIIa CI with rFVIIa BI in major surgery in hemophilia patients with inhibitors. Methods: A 10-day, open-label, randomized, multicenter trial was conducted in hemophilia A or B patients (age > 5 yr) with inhibitors to FVIII or FIX who underwent elective major surgery. Patients received rFVIIa as an initial bolus dose of 90 μg/kg followed by intermittent i.v. bolus (90 μg/kg) or i.v. continuous (50 μg/kg/hr) infusion. BI was administered every 2 hours during surgery and through Day 5, then every 4 hours for Days 6 to 10. CI was administered at 50 μg/kg/hr through Day 5 and at 25 μg/kg/hr Days 6 to10. A third control group of 10 non-inhibitor hemophilia A or B patients who underwent similar surgery and were treated with FVIII or FIX (based on current standard of care and physician’s choice) was assessed to compare adverse event and coagulation profiles. Safety was assessed throughout the study periods. Efficacy was defined as having no treatment failures during the given time and was evaluated at 48 hours, 5 days, and 10 days postoperatively. Treatment was considered ineffective in patients who received more than 2 additional doses of rFVIIa beyond the protocol-defined doses during a 24 hour period. Patients who received alternative hemostatic therapy following the permitted two additional doses of rFVIIa were considered treatment failures. Results: Twenty-four patients (12 CI arm, 12 BI arm) underwent 9 major types of surgeries. Knee (n=11) and hip (n=3) replacements were the most common surgeries. Recombinant FVIIa efficacy in major surgeries was 92% (11 CI, 11 BI) at 48 hours; 83% (10 CI) and 92% (11 BI) at Day 5; 83% (10 CI) and 75% (9 BI) at Day 10. Sixty-six rescue doses (rFVIIa, 90 μg/kg) were administered in the CI group (54 in one patient), and 7 in 3 patients in the BI group. Adverse events occurred more frequently in the CI treatment group (239; 141 in one patient) compared to the BI group (89 AEs); 64 AEs occurred in the control group. Eight patients (3 CI, 4 BI, 1 control) experienced 10 serious adverse events (SAEs). SAEs occurred most frequently in the BI treatment group (3 CI, 6 BI, 1 control). The types of SAEs were equally distributed among the three groups. There were no serious thromboembolic events reported during the study. Conclusions: This summary of 24 major surgeries indicates that rFVIIa is effective as prophylactic therapy for major surgery in hemophilia A or B patients with inhibitors. The numbers of patients were too small to distinguish efficacy rates between the two groups. The safety profile for patients treated with rFVIIa (BI or CI) was similar to the profile for non-inhibitor patients treated with other factors. Presented on behalf of the NovoSeven in Surgery Study Investigators.

IntroductionCentral venous access devices (CVADs) are frequently required as stable long‐lasting venous access in children with haemophilia, especially those requiring immune tolerance induction (ITI) for inhibitors. CVAD infection is one of the most frequently reported catheter‐related complications in this patient population.AimDetailed review of CVAD complications from the International ITI (I‐ITI) study and analysis of potential risk factors for such complications.MethodsRetrospective analysis of prospectively obtained data from the I‐ITI study primarily focused on CVAD‐related complications.ResultsA total of 115 children were recruited and 183 CVADs were placed in 99 subjects resulting in 121,206 CVAD‐days observed on‐study. A total of 124 CVAD infections were reported in 41 of 99 (41%) subjects with an overall infection rate of 0.94 per 1000 CVAD‐days (interquartile ranges 0–1.7). A similar number of infections were observed in the two treatment arms (median: 2 and 3 in high dose and low dose respectively). Infections occurred more frequently in the presence of external catheters than with fully implanted catheters (P = 0.026). Infected patients were significantly younger at the time of CVAD insertion (median age: 22 vs. 25 months, P = 0.020). Patients with Gram‐positive infections were also significantly younger than those with Gram‐negative infections (median age: 17 vs. 25 months, P < 0.0001).ConclusionCVAD infection was the most common complication observed in children with severe haemophilia and inhibitors in the frame of the I‐ITI study. Younger age at CVAD insertion and external CVAD were associated with higher risk for infection. ITI outcome was unaffected by CVAD infections.

SummaryNeonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty‐eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty‐two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1–2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3–5 (16%; n = 10) and 6–10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence‐based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia.